This invention relates to amide compounds and salts thereof which are useful as a medicament.
This invention relates to amide compounds and salts thereof.
More particularly, it relates to amide compounds and salts thereof which have the potentiation of the cholinergic activity, to processes for the preparation thereof, to a pharmaceutical composition comprising the same, and to a method for the treatment and/or prevention of disorders in the central nervous system for mammals, and more particularly to method for the treatment and/or prevention of amnesia, dementia (e.g. senile dementia, Alzheimer""s dementia, dementia associated with various diseases such as cerebral vascular dementia, cerebral post-traumatic dementia, dementia due to brain tumor, dementia due to chronic subdural hematoma, dementia due to normal pressure hydrocephalus, post-meningitis dementia, Parkinson""s disease type dementia, etc.), and the like. Additionally, the object compound is expected to be useful as therapeutical and/or preventive agents for schizophrenia, depression, stroke, head injury, nicotine withdrawal, spinal cord injury, anxiety, pollakiuria, incontinence of urine, myotonic dystrophy, attention deficit hyperactivity disorder, excessive daytime sleepiness (narcolepsy), Parkinson""s disease or autism.
One object of this invention is to provide new and useful amide compounds and salts thereof which possess the potentiation of the cholinergic activity.
Another object of this invention is to provide processes for preparation of the amide compounds and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said amide compounds and salt thereof.
Still further object of this invention is to provide a therapeutic method for the treatment and/or prevention of aforesaid diseases in mammals, using the amide compounds and salts thereof.
The amide compounds of this invention can be represented by the following general formula [I]: 
wherein
R1 and R2 are each aryl or ar(lower)alkyl, or are taken together to form lower alkylene or lower alkenylene, each of which may be substituted with aryl or may be condensed with a cyclic hydrocarbon optionally substituted with lower alkyl, lower alkoxy, aryl, aryloxy or halogen,
R3 is lower alkyl, lower alkoxy, aryl, arylamino or aryloxy, each of which may be substituted with lower alkoxy or halogen, pyridyl, or pyridylamino,
X is CH or N,
Y is a single bond or xe2x80x94NHxe2x80x94, and
Q is 
and salts thereof.
The object compound [I] or its salt can be prepared by processes as illustrated in the following reaction schemes. 
wherein
R1, R2, R3, X and Q are each as defined above, and
R4 is aryl which may be substituted with lower alkoxy or halogen, or pyridyl.
In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following.
The term xe2x80x9clowerxe2x80x9d is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
Suitable xe2x80x9clower alkylxe2x80x9d and lower alkyl moiety in the term xe2x80x9car(lower)alkylxe2x80x9d may be a straight or branched C1-C6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, ethylpropyl, hexyl or the like, in which preferable one is methyl.
Suitable xe2x80x9carylxe2x80x9d and aryl or ar moiety in the terms xe2x80x9car(lower)alkylxe2x80x9d, xe2x80x9caryloxyxe2x80x9d and xe2x80x9carylaminoxe2x80x9d may be phenyl, naphthyl, pentyl substituted with lower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl, di(tert-butyl)phenyl, etc.] and the like, in which preferable one is phenyl.
Suitable xe2x80x9chalogenxe2x80x9d may be fluorine, chlorine, bromine and iodine, in which preferable one is fluorine.
Suitable xe2x80x9car(lower)alkylxe2x80x9d may be benzyl, phenethyl, phenylpropyl, benzhydryl, trityl and the like, in which preferable one is benzyl.
Suitable xe2x80x9clower alkylenexe2x80x9d may be a straight or branched C1-C6 alkylene such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, methylpentamethylene or the like, in which preferable one is tetramethylene or pentamethylene.
Suitable xe2x80x9clower alkenylenexe2x80x9d may be a straight or branched C2-C6 alkenylene such as vinylene, propenylene, butenylene, pentenylene, methylpentenylene, hexenylene, pentadienylene or the like, in which preferable one is butenylene, pentenylene or methylpentenylene.
Suitable xe2x80x9clower alkoxyxe2x80x9d may be a straight or branched C1-C6 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, methylpropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, in which preferable one is methoxy.
Suitable xe2x80x9ccyclic hydrocarbonxe2x80x9d may be a saturated or unsaturated cyclic hydrocarbon such as cyclopentane, cyclohexane, benzene, naphthalene, indan, indene or the like, in which preferable one is benzene.
Preferred compound [I] is one having aryl or ar(lower)alkyl for R1, aryl or ar(lower)alkyl for R2, aryl or arylamino, each of which may be substituted with halogen for R3, CH or N for X, a single bond or xe2x80x94NHxe2x80x94 for Y, and 
for Q; or one having lower alkenylene which may be substituted with aryl or may be condensed with benzene optionally substituted with lower alkoxy for R1 and R2 to be taken together to form, aryl or arylamino, each of which may be substituted with halogen, pyridyl, or pyridylamino for R3, CH or N for X, a single bond or xe2x80x94NHxe2x80x94 for Y, and 
for Q.
Suitable salts of the object compound [I] are pharmaceutically acceptable conventional non-toxic salts and include acid addition salt such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], a salt with an amino acid [e.g. aspartic acid salt, glutamic acid salt, etc.], a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.] and alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.] and the like.
The processes for preparing the object compound [I] are explained in detail in the following.
Process 1
The compound [Ia] or its salt can be prepared by reacting a compound [II] or its salt with a compound [III] or its reactive derivative at the carboxy group or a salt thereof.
Suitable salts of the compounds [Ia] and [II] may be the same as those exemplified for the compound [I].
Suitable salts of the compound [III] and its reactive derivative at the carboxy group may be metal salt or alkaline earth metal salt as exemplified for the compound [I].
Suitable reactive derivative at the carboxy group or the compound [III] may include an ester, an acid halide, an acid anhydride and the like. The suitable examples of the reactive derivatives may be an acid halide [e.g. acid chloride, acid bromide, etc.]; a symmetrical acid anhydride; a mixed acid anhydride with an acid such as aliphatic carboxylic acid [e.g. acetic acid, pivalic acid, etc.], substituted phosphoric acid [e.g. dialkylphosphoric acid, diphenylphosphoric acid, etc.]; an ester such as substituted or unsubstituted lower alkyl ester [e.g. methyl ester, ethyl ester, propyl ester, hexyl ester, trichloromethyl ester, etc.], substituted or unsubstituted ar(lower)alkyl ester [e.g. benzyl ester, benzhydryl ester, p-chlorobenzyl ester, etc.], substituted or unsubstituted aryl ester [e.g. phenyl ester, tolyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, naphthyl ester, etc.], or an ester with N,N-dimethylhydroxylamine, N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxybenzotriazole, 1-hydroxy-6-chloro-1H-benzotriazole, or the like. These reactive derivatives can be optionally selected according to the kind of the compound [III] to be used.
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, chloroform, methylene chloride, ethylene dichloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. Among these solvents, hydrophilic solvent may be used in a mixture with water.
The reaction is also preferably carried out in the presence of a conventional base such as triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, etc., or a mixture thereof.
When the compound [III] is used in a free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide, N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide, N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide, thionyl chloride, oxalyl chloride, lower alkoxycarbonyl halide [e.g. ethyl chloroformate, isobutyl chloroformate, etc.], 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, or the like.
The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
Process 2
The compound [Ib] or its salt can be prepared by reacting a compound [II] or its salt with a compound [IV].
Suitable salts of the compounds [Ib] and [II] may be the same as those exemplified for the compound [I].
This reaction is usually carried out in a solvent such as dioxane, tetrahydrofuran, benzene, toluene, chloroform, methylene chloride or any other organic solvent which does not adversely influence the reaction.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
Process 3
The compound [Ic] or its salt can be prepared by reacting a compound [V] or its salt with a compound [III] or its reactive derivative at the carboxy group or a salt thereof.
Suitable salts of the compounds [Ic] and [V] may be the same as those exemplified for the compound [I].
Suitable salts of the compound [III] and its reactive derivative at the carboxy group may be metal salt or alkaline earth metal salt as exemplified for the compound [I].
This reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 1.
Process 4
The compound [Id] or its salt can be prepared by reacting a compound [V] or its salt with a compound [IV].
Suitable salts of the compounds [Id] and [V] may be the same as those exemplified for the compound [I].
This reaction can be carried out in substantially the same manner as Process 2, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those explained in Process 2.
Process 5
The compound [Ie] or its salt can be prepared by reacting a compound [VI] or its reactive derivative at the carboxy group, or a salt thereof with a compound [VII] or its salt.
Suitable salts of the compounds [Ie], [VI] and its reactive derivative at the carboxy may be the same as those exemplified for the compound [I].
Suitable salt of the compound [VII] may be acid addition salt as exemplified for the compound [I].
This reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process 1.
The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.
It is to be noted that the compound [I] and the other compounds may include one or more stereoisomer(s) such as optical isomer(s) or geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s), and all of such isomers and mixture thereof are included within the scope of this invention.
Additionally, it is to be noted that any solvate [e.g. enclosure compound (e.g. hydrate, ethanolate, etc.)] of the compound [I] or a salt thereof is also included within the scope of this invention.
The object compound [I] and salts thereof possess strong potentiation of the cholinergic activity, and are useful for the treatment and/or prevention of disorders in the central nervous system for mammals, and more particularly of amnesia, dementia (e.g. senile dementia, Alzheimer""s dementia, dementia associated with various diseases such as cerebral vascular dementia, cerebral post-traumatic dementia, dementia due to brain tumor, dementia due to chronic subdural hematoma, dementia due to normal pressure hydrocephalus, post-meningitis dementia, Parkinson""s disease type dementia, etc.) and the like. Additionally, the object compound is expected to be useful as therapeutical and/or preventive agents for schizophrenia, depression, stroke, head injury, nicotine withdrawal, spinal cord injury, anxiety, pollakiuria, incontinence of urine, myotonic dystrophy, attention deficit hyperactivity disorder, excessive daytime sleepiness (narcolepsy), Parkinson""s disease or autism.
In order to illustrate the usefulness of the object compound [I], the pharmacological data of the compound [I] is shown in the following.
Test
Penile erection in rat
(This test was carried out according to a similar manner to that described in Jpn. J. Pharmacol., Vol. 64, 147-153 (1994))
(i) Method
Male Fischer 344 rats at the age of 8 weeks (n=7) were used. All rats were handled 3 minutes a day for three successive days before the tests. The rats were tested in groups of seven and various doses of the test compound were given in semi-randomized order. The test compounds were suspended in 0.5% methyl-cellulose immediately before use, and given intraperitoneally in a volume of 1 ml/kg just before the start of test. Immediately after injection, each rat was placed in a perspex box (25xc3x9725xc3x9735 cm) and its behavior was observed for 60 minutes, during which time the number of penile erections was counted. A mirror was situated behind each box to facilate of the rat. Data was expressed as a mean number.
(ii) Test Result
It is clear that the compound having the above-mentioned activity ameliorates the memory deficits (i.e. amnesia, dementia, etc.) from the description in the Journal of Pharmacology and Experimental Therapeutics, Vo. 279, No. 3, 1157-1173 (1996). Further, it is expected that the compound having the above-mentioned activity is useful as therapeutical and/or preventive agent for aforesaid diseases from some patent applications (e.g. PCT International Publication No. WO 98/27930, etc.).
For therapeutic purpose, the compound [I] and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for oral or parenteral administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, suppositories, solution, suspension, emulsion, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
While the dosage of the compound [I] will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound [I] may be effective for treating the above-mentioned diseases. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
The following Preparations and Examples are given for the purpose of illustrating this invention.
Preparation 1
To a solution of 4-methylcyclohex-3-enecarbonyl chloride (2 ml) in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml) was added aqueous sodium hydroxide (4N, 20 ml). The resultant mixture was stirred at ambient temperature for 1 hour, and evaporated. The residue was taken up into a mixture of water and ethyl acetate and adjusted pH to around 1. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give 4-methylcyclohex-3-enecarboxylic acid, which was used without further purification.
NMR (DMSO-d6, xcex4): 1.60 (3H, s), 1.35-1.65 (1H, m), 1.75-2.2 (5H, m), 2.25-2.45 (1H, m), 5.25-5.4 (1H, m), 12.09 (1H, br s)
MASS (LD)(m/z): 139.2
Preparation 2
To a solution of 4-methylcyclohex-3-enecarboxylic acid (1.7 g) and triethylamine (1.8 ml) in tert-butanol (35 ml) was added diphenylphospholyl azide (2.6 ml), and the mixture was refluxed for 8 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate, washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate, and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was chromatographed on silica gel (150 ml) eluting with 1-3% ethyl acetate in n-hexane to give 1-tert-butoxycarbonylamino-4-methylcyclohex-3-ene (0.82 g).
NMR (DMSO-d6, xcex4): 1.37 (9H, s), 1.60 (3H, s), 1.65-2.2 (6H, m), 3.2-3.4 (1H, m), 5.2-5.3 (1H, m), 6.68 (1H, br s)
MASS (LD)(m/z): 234.3
Preparation 3
To a solution of 1-tert-butoxycarbonylamino-4-methylcyclohex-3-ene (0.4 g) in a mixture of anisole (0.4 ml) and dichloromethane (0.8 ml) was added trifluoroacetic acid (1.2 ml) at 0xc2x0 C. and the mixture was allowed to stir at 0xc2x0 C. for 1 hour. Evaporation gave a residue, which was taken up into a solution of hydrogen chloride in dioxane (4N, 2 ml). Evaporation under reduced pressure and trituration with diisopropyl ether gave 1-amino-4-methylcyclohex-3-ene hydrochloride, which was used without further purification.